Nebulized or Sprayed Cidofovir for Recurrent Respiratory Papillomatosis

ABSTRACT

A solution of 2.5-20% cidofovir is administered as droplets having a mean size of about 1 micron to about 20 microns either nebulized or as a spray to an individual having recurrent respiratory papillomatosis.

PRIOR APPLICATION INFORMATION

The instant application claims the benefit of U.S. Provisional PatentApplication 60/948,877, filed Jul. 10, 2007.

BACKGROUND OF THE INVENTION

Recurrent Respiratory Papillomatosis (RRP) is a rare albeit severeairway management problem in the pediatric population. Extremelydifficult to treat, patients usually undergo multiple surgicalprocedures and toxic systemic medications in an attempt to control theirdisease.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided a methodof treating recurrent respiratory papillomatosis comprising orallyadministering a solution of 2.5-20% cidofovir as droplets having a meansize of about 1 micron to about 20 microns to an individual in need ofsuch treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Pre-topical Cidofovir

FIG. 2: Topical & nebulized Cidofovir

FIG. 3: CT scans pre & post Cidofovir

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications mentioned hereunderare incorporated herein by reference.

Recurrent Respiratory Papillomatosis (RRP) is a disease caused by avirus, the Human Papillomavirus (HPV). HPV, which causes warts, has manysub-types, some which are responsible for genital warts, abnormalchanges on women's cervix leading to cervical cancer (therefore asexually transmitted disease) and RRP. Traditionally, the treatment forthese warts (papillomas) has been surgical removal.

Surgical removal of papillomas in the airways must occur in theoperating room with the patient under general anesthetic. Typically,however, the papillomas recur. Most patients require only infrequentremoval of papillomas, especially those whose papillomas only occur ontheir vocal cords, only undergoing surgical removal when symptoms of thepapilloma affects voice quality or becomes an obstruction to breathing.A minority of these patients have papillomas below their vocal cords,which infect the lower airways and even the lung itself. For thosepatients, breathing is severely affected, operations to remove thepapillomas more risky, and subsequently, there is a high chance ofdeveloping lung cancer leading to untimely death.

As will be apparent to one of skill in the art, surgical procedures inthe airways involve considerable risk. First, there is the risk of theanesthetic itself. Second, when one uses surgical instruments in theairway, the airway itself is partially blocked, reducing airflow andoxygen to the lungs. The airways are vascular and can bleed easily. Inaddition, most surgical procedures to remove papillomas necessitate theuse of rigid hollow tubes which realistically cannot reach into thelower airways (which branch from the main airway, the trachea). Thismeans that papillomas in the lower airways are not easily reached byconventional methods, and if attempted carries higher risk to thepatient. Furthermore, the smaller the patient, the greater the risk.

Adjunctive therapy has been tried for papillomas in the airways withlimited success. The best success has occurred with injecting anantiviral drug, cidofovir, directly into the papillomas at the vocalcord level. However, direct injection into papillomas in the lowerairways is close to impossible due to surgical constraints.

Topical cidofovir has been used as a gel to treat lesions on the skin.In AIDS patients, gel-based cidofovir has been used to control herpesskin infections with success. However, the gel cannot be used in theairways due to its chemical composition.

For our patient, her small size made surgical removal of the papillomasin her lower airways close to impossible, injecting cidofovir impossibleand she was failing intravenous therapy.

We decided that applying cidofovir using a flexible bronchoscope and acytology brush soaked in cidofovir would be a reasonable method toattempt to deliver the drug to the papillomas. We used the intravenousform of the drug, diluted to the concentration used in the gel basedformula. Initially, the drug did not stick well to the brush, so wethickened it with glycerine so that the drug would “stick” first to thebrush, then to the papilloma. This preparation worked to reduce the sizeof the papillomas.

Although a success, the topical application of cidofovir was not withoutrisk. The papillomas required “brushing” every 2 weeks to continue tosee the effect of the drug. This required a general anesthetic every 2weeks, which as discussed above is not without risk to the patient.Additionally, the application of the cytology brush through a flexiblebronchoscope (which when in use reduced the patient's effective airwaysize to <25%) could potentially lead to complications such as hypoxia(low oxygen levels) and bleeding. Additionally, at one point thecytology brush got ‘stuck’ in the papilloma and was difficult to remove.We clearly needed a better strategy.

Other airway diseases, such as asthma, are treated with inhaled drugs,such as steroids. Infections of the airways in patients with CysticFibrosis are treated with nebulized antibiotics. We thought, why notthis? Our Clinical Pharmacologist contacted the maker of cidofovir, whorefused to discuss options for delivering the drug in this fashion.Therefore, we did it ourselves.

Nebulized drugs are administered by breaking up a solution of drug in amedication cup that has forced air going through it, making a “mist”. Ifthe amount of solution in the medication cup has 4 ml in it, theresulting droplet size is 2-4 microns in diameter, the right size todeposit the drug into the airways after the main airway (trachea). Somedrug will deposit more proximal (trachea) but the bulk of the drugdeposits in the lower airways. Therefore, we made a 4 ml solution at thesame concentration we were using for the topical application. This hadnumerous benefits for our patient: no more frequent trips to theoperating room, the drug could be delivered more frequently, the drugcould be administered at home, and obvious reduction of significantoperative risks. Additionally, the drug could reach those airways whichwere unreachable by surgical means.

The nebulized drug worked well. It reached those areas previouslyunreachable. In fact, we even saw improvement in the lung (as evidencedby CT scans of the lung). However, as predicted, based on droplet size,the papillomas in the main airway (trachea) remained large. In our firstpatients' case, this was tackled with surgical removal and the topicalapplication of our glycerine based cidofovir to the bare base of thepapillomas. She is now papilloma free.

The nebulized form of cidofovir is meant for application of the drug inthose patients whose disease is in the lower airways. However, toadminister this drug, in this fashion, to those who only have papillomason their vocal cords (or higher in the airway) is inappropriate. First,the drug goes to the wrong area of the airways. Second, this drug is notwithout known side effects: for example, the main side effect weencountered was bleeding (dose dependent & related to infection withbacteria, typically Pseudomomas aeruginosa). We were also worried aboutpotential bronchospasm (asthma like closure of the airways) as ourpatient did exhibit cough with the drug. To expose someone tosignificant side effects like this was unacceptable.

Consequently, we then developed a spray solution of cidofovir, using thesame concentration as described above. In some embodiments, a flavouringagent, for example, an addition of mint flavouring (can be adjusted tomeet individual tastes and as such other flavourings known in the artmay be utilized in the invention). In a preferred embodiment, thedispenser includes a long nozzle, which can be used to target the spraydirectly toward the papillomas on the vocal cords (or higher) withoutthe worry of a significant amount of drug reaching the trachea or lowerairways. In these embodiments, the droplets of cidofovir may have anaverage size of about 16 microns±3 microns.

During flexible bronchoscopy, where an endoscope is placed via the nares(nose) or through the mouth, the Bronchoscopist must ‘freeze’ the vocalcords and the subsequent trachea and lower airways to diminish the coughreflex (think of a piece of food going the wrong way, one coughsviolently to prevent the food from going into the lungs). As aBronchoscopist, I squirt Xylocalne (the same drug the dentist uses tofreeze the mouth), onto the vocal cords, then I spray Xylocalneimmediately after passing the vocal cords to freeze the trachea andlower airways. Just freezing the vocal cords does not prevent the coughfrom the trachea.

Therefore, we know that the spray cidofovir will only affect the vocalcords, and the nebulized form mainly deposits in the lower airways. Thespray form is for the patient with isolated papillomas at the level ofthe vocal cords or higher, the nebulized form is for those with distalairway & lung involvement.

The topical preparation is 10% based in sterile glycerine. Dosing isvariable, but at the time of surgery.

The concentration for nebulization is 2.5%-20%. It is diluted in sterilenormal (0.9%) saline (NaCl) in a Class II laminar flow biologic safelyhood. Cytotoxic precautions are taken. Dosing is 2-3 times/week (Daily qMonday, Wednesday & Friday).

The concentration for spray is 2.5%-20%. It is diluted in sterile normal(0.9%) saline (NaCl) in a Class II laminar flow biologic safely hood.Cytotoxic precautions are taken. Flavouring is added to make it morepalatable. Dosing is daily×5 (Monday-Friday).

In other embodiments, other pharmaceutically acceptable diluentscompatible with cidofovir may be used in place of saline. It is notedthat such agents will be readily apparent to one of skill in the art.

Accordingly, in one embodiment of the invention, there is provided amethod of treating recurrent respiratory papillomatosis comprisingorally administering a solution of 2.5-20% cidofovir as droplets havinga mean size of about 1 micron to about 20 microns to an individual inneed of such treatment.

As will be appreciated by one of skill in the art, as used herein, ‘anindividual in need of such treatment’ is an individual who has or issuspected of having recurrent respiratory papillomatosis, that is, ahuman papillomavirus infection of the airway.

As discussed above, in a preferred embodiment, the droplets have a meandiameter of approximately 12-20 microns or of approximately 13-19microns for treatment of papillomas proximal to the vocal cords.

In other embodiments, the droplets have a mean diameter of approximately1-4 microns for treatment of the airways after or below the main airway(trachea).

It is of note that other suitable diameters for distribution to otherparts of the airway may be used and are within the scope of theinvention as these may be determined by routine experimentation.

As will be appreciated by one of skill in the art, 0.25-20% cidofovirrepresents an effective amount of cidofovir in that it will accomplishat least one of the following: reduction of papilloma size, longerperiods of remission or being symptom-free, improved breathing as wellas other benefits which will be readily apparent to one skilled in theart.

Herein we report the use of nebulized cidofovir to treat RRP disease ina young girl without significant side effects. E presented at 11 monthsof age with respiratory failure and stridor. She was found to havelaryngeal papillomas; her lesions completely obscured her upper airway.A tracheostomy was done for airway protection and it was discovered thather disease extended distally. Multiple surgical procedures failed toalleviate the lesions. Usual medical therapy (Interferon and Cidofovir)did not halt the progression of the disease; in fact, her lesionsworsened especially in the right main bronchus. We elected to applytopical Cidofovir to her lower airway lesions citing literature tosuggest that this approach was useful in other viral based lesions.Initially, Cidofovir (modified in sterile glycerin) was applied directlyvia flexible bronchoscopy every 2 weeks with good results. The lesionsregressed with this technique. However, the lung papillomas could not betreated by this method. Therefore, we elected to nebulize the drug(Cidofovir 10 mg/ml in NS, 4 cc, 3 times/week). Her only complicationwas hemoptysis that resolved with decreasing the dose. Her lower airwaylesions responded currently her lower airway lesions have visuallydisappeared. She is maintained on Cidofovir 2 times/week withoutcomplications. Nebulized Cidofovir appears to be a safe practicaltreatment for severe RRP.

The invention will now be described by way of examples; however, theinvention is not necessarily limited by the examples.

EXAMPLE 1 Nebulized Form Case Report:

Background: Miss E is an ex-prem (24 week GA) born to a 17 year old momwho had antenatal bleeding and had been given steroids prior todelivery. Her postnatal course was complicated by Respiratory distresssyndrome (mechanical ventilation for 52 days, CPAP for 28 days and O₂for 30 days), a patent ductus arteriousus (indomethacin & surgicalligation), hemodynamic instability necessitating inotropic support andrenal failure. Following discharge home Miss E had severe GERD, (L)inguinal hernia repair and was described to have colic. She had a “poor”or “weak” cry and “mild” stridor that was presumed to be secondary tovocal cord paresis or paralysis (although not confirmed by directlaryngoscopy).

Presentation: At 10½ months of age, she presented to the Children'sHospital Emergency Room with increasing difficulties breathing. Herstridor had worsened, she had obvious shortness of breath and had anaudible wheeze. She was admitted to hospital and subsequentlytransferred to the Pediatric intensive care unit. She was diagnosed withupper airway obstruction and treated with Heliox (80:20) and nebulizedracemic epinephrine. She developed Type II respiratory failure (pCO2 62mm Hg) and was intubated for further respiratory support. It was notedthat she had “verrucous growths on vocal cords & aryepiglottic region”.Direct laryngoscopy & bronchoscopy confirmed the diagnosis ofPapillomatosis and with lesions in the proximal trachea (FIG. 1 a). Sheunderwent tracheostomy. Pathology confirmed the diagnosis ofpapillomatosis due to Human Papillomavirus subtype 6 (HPV-6).

Initial management: Suspension laryngoscopy with CO₂ laser for debulkingpapillomas was performed ×6 (locally) and ×2 (larger tertiary centre)(FIG. 1 b). Her lesions were described as “confluent papillomas coveringthe larynx, trachea, proximal main bronchi & proximal esophagus”. CTscan of the chest suggested distal spread of the papillomas (FIG. 3 a).Palliation was discussed with the mother.

Adjuvant therapy: Medical management was initiated 6 months intotreatment. Cidofovir was started (4.1 mg/kg/dose) every 4 weeks withouteffect. The regime was stepped-up to q2 weeks and Interferon α2b wasadded (5 MU/m² 3× weekly). Although her disease had ‘stabilized’ for 3months (no surgical interventions required) her cidofovir dose wasstepped down to q3 weeks due to concerns about renal toxicity and thelesions worsened. The cidofovir dose was stepped-up again (q2 weeks) butthe disease continued to progress (FIG. 1 c).

Topical and nebulized cidofovir: The patient was started on topicallyapplied cidofovir via flexible bronchoscopy q2 weeks in addition tocontinuing the intravenous (systemic) dose. A cytology brush was soakedin cidofovir 10 mg/ml solution and advanced via the bronchoscope to thelower airway papillomas (FIG. 2 a). We elected to start nebulizedcidofovir to reduce the frequency of Bronchoscopic procedures and tointensify treatment. Cidofovir 10 mg/ml 4 ml (total dose 40 mg) wasnebulized via Pari-nebulizer® 3× weekly but complications ensued(bleeding and protracted airways inflammation). The dose was halved (5mg/ml) with resolution of the complications and reduction of the burdenof the papillomas (FIG. 2 b). After 6 months of nebulized cidofovir, thedose was reduced to 2× weekly.

Current status: A large papilloma was surgically debulked(microdebridment) and topical cidofovir was topically applied to thebase of the lesion. Her disease has remitted and she has beensuccessfully decannulated. She undergoes surveillance bronchoscopy q3months and continues on nebulized cidofovir 5 mg/ml, 4 cc 2× weekly(FIGS. 2 c and 3 b).

While the preferred embodiments of the invention have been describedabove, it will be recognized and understood that various modificationsmay be made therein, and the appended claims are intended to cover allsuch modifications which may fall within the spirit and scope of theinvention.

1. A method of treating recurrent respiratory papillomatosis comprisingorally administering a solution of 2.5-20% cidofovir as droplets havinga mean size of about 1 micron to about 20 microns to an individual inneed of such treatment.